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Investigations into the mechanisms underlying the increase in glucose-dependent insulin secretion during DHA/EPA stimulation in pancreatic beta cells.

Research Project

Project/Area Number 16K18997
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field General physiology
Research InstitutionUniversity of Fukui (2017-2018)
Ritsumeikan University (2016)

Principal Investigator

Takeda Yukari  福井大学, 学術研究院医学系部門, 助教 (20582159)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords受容体・細胞内シグナル伝達
Outline of Final Research Achievements

Activation of GPR40 by long-chain fatty acids, EPA and DHA, increase glucose-stimulated insulin secretion from pancreatic beta cells. The current study demonstrated that simultaneous activation of GPR40 and GLP-1 receptor (R) signal transduction cascades (PKC pathway and PKA pathway) synergistically increased insulin secretion from INS-1. The effect was completely abolished by a PKA inhibitor, H-89 alone, suggesting crosstalk between GPR40 and GLP-1R signaling systems. Interestingly, the insulinotropic effect of PKC is also inhibited by H-89. It indicates that pre-phosphorylation of the PKC effector by PKA at a basal cAMP level, is fundamental to the PKC effect. Mathematical analysis suggested that IP3R is the key target effector of the crosstalk between GPR40 and GLP-1 receptor (R) signaling pathways.

Academic Significance and Societal Importance of the Research Achievements

二型糖尿病患者が世界的に増加の一途をたどる中、GPR40刺激が血糖値依存的にインスリン分泌を増強することから、二型糖尿病治療の新たな薬剤標的として近年注目を浴びている。一方で、武田薬品工業が生成したGPR40合成作動薬TAK-875は、肝機能異常を伴うため新たな薬剤の探索が急務であるとされていた。本研究ではIP3Rが二型糖尿病治療の新たな標的となる可能性を示した。また、GLP-1R・GPR40シグナル伝達系の同時刺激よるIP3Rの相乗的な活性化は、魚類などEPAを多く含む食事療法やサプリメントの摂取で実現できる可能性があり、安心・安全な糖尿病治療に貢献できると期待する。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (8 results)

All 2017 2016

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Acknowledgement Compliant: 1 results) Presentation (5 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results)

  • [Journal Article] Theoretical investigations into the quantitative mechanisms underlying the regulation of [cAMP]i, membrane excitability and [Ca2+]i during GLP-1 stimulation in pancreatic β-cells.2016

    • Author(s)
      Yukari Takeda
    • Journal Title

      Yakugaku-Zasshi

      Volume: 136(3) Pages: 467-471

    • NAID

      130005131244

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Modeling analysis of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization under the control of glucagon-like peptide-1 in mouse pancreatic beta cells.2016

    • Author(s)
      Takeda Y., Shimayoshi T, Holz GG, Noma A
    • Journal Title

      Am. J. Physiol. Cell Physiol.

      Volume: 310(5)

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Theoretical Analysis of the mechanisms underlying incretin-induced amplification of insulin secretion2016

    • Author(s)
      Yukari Takeda
    • Journal Title

      BIO Clinica

      Volume: Incretin-Resent topics Pages: 88-90

    • Related Report
      2016 Research-status Report
  • [Presentation] Quantitative Modeling and Simulation Analysis of Membrance Excitability and [Ca2+]i Dynamics Under the Control of GLP-1 in Pancreatic β-Cells2017

    • Author(s)
      Yukari Takeda
    • Organizer
      18th Servier-IGIS Symposium
    • Place of Presentation
      St Jean Cap Ferrat, France
    • Year and Date
      2017-03-25
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] A photoreceptor model considering regulation of ionic homeostasis2017

    • Author(s)
      Saya Ito
    • Organizer
      Biophysical Society 61st Annual Meeting
    • Place of Presentation
      Louisiana, USA
    • Year and Date
      2017-02-15
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Simulation analysis of phototransduction systems in rods and cones2017

    • Author(s)
      Kazuma sato
    • Organizer
      Biophysical Society 61st Annual Meeting
    • Place of Presentation
      Louisiana, USA
    • Year and Date
      2017-02-15
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 膵β細胞におけるGLP-1受容体刺激によるイノシトール三リン酸受容体を介するCa2+動員制御機構の理論研究2016

    • Author(s)
      竹田有加里
    • Organizer
      第59回日本糖尿病学会年次学術集会
    • Place of Presentation
      国立京都国際会館(京都府、京都市)
    • Year and Date
      2016-05-21
    • Related Report
      2016 Research-status Report
  • [Presentation] Modeling analysis of IP3R-mediated Ca2+ mobilization under the control of GLP-1 in mouse pancreatic beta cells2016

    • Author(s)
      Yukari Takeda
    • Organizer
      1st Advances & Breakthroughs in Calcium Signaling
    • Place of Presentation
      Hawaii, USA
    • Year and Date
      2016-04-09
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2020-03-30  

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